title: Differential drug-drug interactions of the synthetic Cannabinoids JWH-018 and JWH-073: implications for drug abuse liability and pain therapy.
abstract: Marijuana substitutes often contain blends of multiple psychoactive synthetic cannabinoids (SCBs), including the prevalent SCBs (1-pentyl-1H-indole-3-yl)-1-naphthalenyl-methanone (JWH-018) and (1-butyl-1H-indole-3-yl)-1-naphthalenyl-methanone (JWH-073). Because SCBs are frequently used in combinations, we hypothesized that coadministering multiple SCBs induces synergistic drug-drug interactions. Drug-drug interactions between JWH-018 and JWH-073 were investigated in vivo for Δ(9)-tetrahydrocannabinol (Δ(9)-THC)-like discriminative stimulus effects, analgesia, task disruption, and hypothermia. Combinations (JWH-018:JWH-073) of these drugs were administered to mice in assays of Δ(9)-THC discrimination, tail-immersion, and food-maintained responding, and rectal temperatures were measured. Synergism occurred in the Δ(9)-THC discrimination assay for two constant dose ratio combinations (1:3 and 1:1). A 1:1 and 2:3 dose ratio induced additivity and synergy, respectively, in the tail-immersion assay. Both 1:1 and 2:3 dose ratios were additive for hypothermia, whereas a 1:3 dose ratio induced subadditive suppression of food-maintained responding. In vitro drug-drug interactions were assessed using competition receptor-binding assays employing mouse brain homogenates and cannabinoid 1 receptor (CB1R)-mediated inhibition of adenylyl cyclase activity in Neuro2A wild-type cells. Interestingly, synergy occurred in the competition receptor-binding assay for two dose ratios (1:5 and 1:10), but not in the adenylyl cyclase activity assay (1:5). Altogether, these data indicate that drug-drug interactions between JWH-018 and JWH-073 are effect- and ratio-dependent and may increase the relative potency of marijuana substitutes for subjective Δ(9)-THC-like effects. Combinations may improve the therapeutic profile of cannabinoids, considering that analgesia but not hypothermia or task disruption was potentiated. Importantly, synergy in the competition receptor-binding assay suggests multiple CB1R-SCB binding sites.
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Brents
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Zimmerman
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Saffell
authors.forename: Paul L
authors.initials: PL
authors.lastname: Prather
authors.forename: William E
authors.initials: WE
authors.lastname: Fantegrossi
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D002478:Cells, Cultured; D003216:Conditioning, Operant / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004357:Drug Synergism; D005260:Female; D005793:Generalization, Psychological / Q000187:drug effects; D007035:Hypothermia / Q000139:chemically induced / Q000503:physiopathology; D013287:Illicit Drugs; D066298:In Vitro Techniques; D007211:Indoles / Q000009:adverse effects* / Q000627:therapeutic use*; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009281:Naphthalenes / Q000009:adverse effects* / Q000627:therapeutic use*; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects; D019966:Substance-Related Disorders
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D013287:Illicit Drugs; D007211:Indoles; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; C568258:JWH-073; C552597:1-pentyl-3-(1-naphthoyl)indole